[unreadable] The mechanism of brain dysfunction by drugs is not well characterized. Accessible objective markers to follow the influence of a substance or foreign microbe on the normal brain would be helpful. Cerebrospinal fluid (CSF) provides a liquid window to the brain. We will use a proteogenomic approach to characterize the whole proteome of normal CSF and compare it to HIV-associated dementia (HAD). Markers for this HAD alone would be useful for diagnosis and to monitor' efficacy of therapy. Although autoimmune reactivity to the brain and nervous tissue has been associated with dysfunction in several diseases, this remains an understudied area in HAD. A combined strategy using genomics, proteomics, and immunology has high potential to provide useful markers for HAD. Recently we found a significant association of antibrain antibodies, reacting to several different molecular weights of non HFV-infected brain. This proposal will use several strategies that may provide complementary and convergent results to identify markers of HAD. For Specific Aim 1, one approach is to identify the sequence of those targets of the antibrain antibodies that have been found already using the banked cerebrospinal fluid (CSF) samples from well characterized HAD patients and controls. Antigens of the molecular masses determined by the antibrain antibodies will be extracted from uninfected whole brain. These antigens will be subjected to enzymatic digestion and mass spectrometry for peptide mapping to identify the antigen by comparison to the human genome. In parallel to this, CSF antigen-antibody complexes will be probed and the antigen subjected to similar proteomic analysis. Specific Aim 2 is directed at identification of novel proteins or ratios of proteins in CSF by comparison of quantitative and qualitative proteomic profiles from HAD patients versus normals. At the very least this will provide a working database to compare disease-CSF to normals. These approaches may prove useful in investigation of this and other diseases such as substance abuse where markers are needed to monitor therapy or to illucidate interactions between drugs and microbes. [unreadable] [unreadable] [unreadable] [unreadable]